Abstract
The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Cell Cycle Proteins
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Cell Line, Tumor / metabolism
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Cell Line, Tumor / transplantation
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Cell-Penetrating Peptides / pharmacology
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / physiology
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Female
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GTP Phosphohydrolases / genetics
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Gene Expression Regulation, Neoplastic
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Humans
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Keratinocytes / metabolism
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Male
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Melanocytes / metabolism
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Melanoma / chemistry*
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Melanoma / pathology
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Melanoma / secondary
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Melanoma, Experimental / etiology
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Melanoma, Experimental / genetics
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Membrane Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Mice, Transgenic
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins c-mdm2 / biosynthesis
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Proto-Oncogene Proteins c-mdm2 / genetics
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Recombinant Fusion Proteins / physiology
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Signal Transduction / physiology
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Skin Neoplasms / chemistry*
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Tumor Stem Cell Assay
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / physiology
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Cell-Penetrating Peptides
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MDM4 protein, human
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Membrane Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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SAH-p53-8 peptide
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TP53 protein, human
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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GTP Phosphohydrolases
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NRAS protein, human